Vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer?s disease related dementias (ADRD) significantly contribute to the 47 million people world-wide who suffer with dementia. This number is estimated to increase to over 130 million people by 2050. A number of studies have shown that VCID and conversion to ADRD are strongly correlated with vascular disease, inflammation and decreased cerebral brain blood flow (1),(2),(3), (4),(5),(6), (7),(8). The relationship between vascular disease, cognitive function and progression to dementia and possible AD have been recently reviewed (9). These authors successfully make the case for a close relationship between cardiovascular risk factors and risk for VCID and ADRD. Furthermore, conversion rates of VCI to dementia has been reported to be within 40-46% within 5 years of diagnosis of VCI (10),(11). To date, there are no approved therapies for VCID. ProNeurogen has been working to develop novel Angiotensin 1-7 (Ang-1?7) formulations to treat inflammation-related cognitive impairment in patients at for risk ADRD and VCID. The goal of the present SBIR Phase I project is to begin feasibility studies to develop an extended release subcutaneous injection formulation for the administration of our novel peptide therapies to treat brain inflammation related cognitive impairment and VCID. These novel peptide formulations are designed to act on Mas receptors (MasR) within the brain vascular endothelium and neuronal cells and microglia to decrease brain ROS production and neuroinflammation. We have begun to translate these preclinical findings into novel peptide therapeutics to treat inflammation related cognitive impairment in patients with heart disease who are at risk for ADRD or VCID. We have an approved FDA IND # 125320 and support for Phase 2a trials for native Ang-(1-7) for treatment of cognitive impairment in heart failure (HF) patients and NIH support for our trial in cardiac bypass surgery patients (CABG). Our current approved treatment protocol for HF/VCID patients is once a day, subcutaneous 100 microg/kg injection using a standard needle and syringe for 85 days in our VCID/HF patients. However, in order to increase patient compliance, as well as accelerate commercialization we are currently investigating new formulations that are more patient friendly and require fewer injections. We will take advantage of Oakwood Labs? extensive experience with extended release formulation of sterile injectables to complete the 2 principal objectives of this project: 1. Objective 1. Complete feasibility studies to develop extended release subcutaneous injection formulation of Ang-(1-7). 2. Objective 2. Complete comparative in vivo PK studies of the extended release injection formulations. Following successful completion of these feasibility studies, in Phase II we will conduct extensive PD studies of the PLGA-Ang-(1-7) formulation in our VCID animal model to establish the cognitive protective and brain anti-inflammatory effects of PLGA-Ang-(1-7) and ultimately begin IND enabling studies.